The present invention relates to new bioresorbable polymers synthesized from monomer analogs of natural metabolites. In particular, the present invention relates to polymers polymerized from analogs of amino acids that contribute advantageous synthesis, processing and material properties to the polymers prepared therefrom, including particularly advantageous degradation profiles.
U.S. Pat. No. 5,099,060 discloses diphenolic monomers based on 3-(4-hydroxy-phenyl) propionic acid and L-tyrosine alkyl esters (desaminotyrosyl-tyrosine alkyl esters). Subsequent related patents involve variations of this basic monomer structure, including halogenated radiopaque diphenolic monomers, such as the 3,5-di-iododesaminotyrosyl-tyrosine esters (I2DTR, wherein R is an alkyl group, e.g., E=ethyl, H=hexyl, O=octyl, etc.) disclosed by U.S. Patent Application Publication No. 20060034769. The disclosures of both publications are incorporated herein by reference. These monomers, although useful in many applications, have several limitations:
In the context of these teachings, the term “degradation” is defined as the process leading to the chemical cleavage of the polymer backbone, resulting in a reduction in polymer molecular weight and mechanical strength. The rate of polymer degradation under physiological conditions is predominantly determined by the type of bonds used to link the individual polymer repeat units together. Hence, polyanhydrides, e.g., polymers containing the highly labile anhydride linkage, will tend to degrade faster than polyesters. In contrast, the term “resorption” is defined as the process leading to a reduction of the mass of an implanted device. The rate of resorption is predominantly governed by the solubility of the polymer itself or its degradation products. The resorption of an implant is complete, once the entire mass of the implant has been removed from the implant site. Degradation and resorption do not always go hand-in-hand. Just for the purpose of providing an illustrative example, a sugar cube in water will “resorb” (e.g., lose mass and ultimately disappear) without any chemical degradation process. Likewise, comparing the degradation and resorption profiles of two different polyanhydrides, one can expect that both polymers will degrade when exposed to aqueous media, but the polymer degrading into more soluble degradation products will be losing mass faster and will, therefore, be the polymer that will resorb faster when implanted in a patient.
Use of monomers having two phenolic hydroxyl groups, as disclosed in the above mentioned Patent Applications, tend to limit the resulting homopolymers to fully aromatic backbone structures. Such polymers have generally good mechanical properties—but slow degradation rates. Moreover, when the monomers are sparingly soluble in water, the degradation products formed during polymer degradation are often also sparingly soluble in water. This property can slow or prevent the degrading polymer from being resorbed at a time scale that is concomitant with polymer degradation. Hence, such polymers will tend to have some use limitations as medical implant materials when the processes of degradation and resorption need to occur concomitantly. The previously described homopolymers prepared from the previously described sparingly-soluble monomers will not have any significant weight loss while the degradation of the homopolymer backbone results in reduction in the polymer molecular weight and loss of mechanical strength. As a result, implantable medical devices and drug delivery implants prepared from the previously described homopolymers that are intended to be resorbed are still substantially undissolved at the end of their useful life as measured by reduction in polymer molecular weight or mechanical strength.
This is particularly a problem for drug delivery implants and implantable medical devices that are intended to be replaced as part of a long-term treatment regimen. For example, a polymeric implant for the delivery of birth control hormones is intended to be replaced at the terminal stage of polymer degradation when essentially all of the hormones have been released as a consequence of polymer backbone degradation and mass loss. However, implants formed with many of the previously described homopolymers will not only be substantially undissolved when a replacement device must be implanted, significant mass will remain when the next replacement device is due for implantation. This creates the untenable situation where patient would be expected to endure having several depleted polymeric drug delivery implants in their body at various stages of resorption while replacement devices continue to be implanted at a periodic rate.
Homopolymers of non-aromatic amino acids have been prepared. Examples are polyglycine, polyalanine, polyserine, polyleucine. However, despite their apparent potential as biomaterials, such poly(amino acids) have actually found few practical applications. A major problem is that most of the poly(amino acids) are highly intractable (e.g., non-processable by conventional thermal or solvent fabrication methods), which limits their utility.
The elegant synthesis of a copolymer derived from lactic acid and lysine was reported by Barrera et al., Macromol., (28), 425-432 (1995). The lysine residue was utilized to chemically attach a cell-adhesion promoting peptide to the copolymer.
Other polymers of amino acids and hydroxy acids are disclosed by U.S. Pat. No. 3,773,737. The non-aromatic copolymers were random copolymers prepared from cyclic monomers by ring-opening polymerization. The composition of the copolymers is highly dependent on the relative reactivity of the two types of cyclic monomers and on the exact polymerization conditions used. It is hard to control the composition and hard to predict the polymer properties. Also, there may be large batch-to-batch variations in the polymer microstructure and sequence. Further, most previous reports only described polymers of relatively low molecular weight (MW<10,000).
There are very few degradable polymers for medical uses that have been successfully commercialized. Poly(glycolic acid) (PGA), poly(lactic acid) (PLA) and their copolymers are representative examples. However, these polymers degrade to form tissue-irritating acids. Polymers of tyrosine and hydroxy acids such as glycolic acid and lactic acid have also been prepared and are disclosed by U.S. Pat. No. 6,284,862. There still remains a need for bioresorbable polymers suitable for use as tissue-compatible materials.
For example, many investigators in the emerging field of tissue engineering have proposed to engineer new tissues by transplanting isolated cell populations on biomaterial scaffolds to create functional new tissues in vivo. Bioresorbable materials whose degradation and resorption rates can be tailored to correspond to the rate of tissue growth are needed. It is desirable that libraries of many different materials be available so that the specific polymer properties can be optimally matched with the requirements of the specific application under development.